Mattingly - Cholinergic Pharmacology IV Flashcards
Dantrolene:
MOA
Use
Action
Site of action
MOA: depresses skeletal muscle contraction by blocking release of Ca++ from the SR of skeletal muscles
Use:
o Spasticity type diseases (ie. patients with UMN lesions where reflex activity through the spinal cord below the lesion results in sustained spastic contractions)
o Adjunct during anesthesia to treat malignant hyperthermia
Action: no effect on ACh release, the motor endplate, or the AP conducted down the sarcolemma
Site of action is INTRACELLULAR
Ganglionic Transmission:
Membrane potential changes in post-ganglionic cell bodies contain at least 3 components:
- Rapid, short-duration EPSP (fEPSP)
- Hyperpolarization (IPSP)
- One or more slower EPSPs of low magnitude
What is the first primary event responsible for ganglionic transmission?
Mediated by?
Blocked by? (2)
Rapid, short-duration EPSP (fEPSP): first primary event responsible for ganglionic transmission
Induces depolarization to fire APs in post-ganglionic neuron
Mediated by nAChRs
Blocked by mecamylamine or d-tubocurarine (results in overall block of ganglionic transmission)
What has the primary role to control/prevent excessive neurotransmission through the ganglia
What mechanisms does IPSP use?
Hyperpolarization (IPSP): primary role to control/prevent excessive neurotransmission through the ganglia; due to several mechanisms
Mechanisms:
DA release from accessory cells in ganglion (SIF cells)
ACh stimulation of inhibitory M2 receptors
One or more slower EPSPs of low magnitude are probably mediated by:
One or more slower EPSPs of low magnitude: probably mediated by a combination of M1 receptors and receptors for peptide co-transmitters
Ganglionic Blockade:
Mechanism
Historic use
Ganglionic Blockade:
Mechanism: selective competitive antagonists at nAChRs on the post-ganglionic cell dendrites and cell body within ganglia
- Blocks both SS and PS ganglionic transmission
Historic Use: some of first effective drugs to treat HTN (reduced SS tone to vasculature)
o Tons of unwanted SEs (notably orthostatic hypotension due to inhibition of postural reflexes)
Ganglionic Blockers: (2)
Structure, use, clinical trials (of the second one)
Hexamethonium: classically used in experiments
Mecamylmine:
Structure: secondary amine
Use: rarely used to treat HTN anymore
- Some use in hypertensive emergencies
- Some use in producing controlled hypotension during neurosurgery
Clinical trials: currently being tested for treatment of certain nicotine-sensitive CNS disorders (ie. Tourette’s Syndrome)
CHOLINESTERASE INHIBITION:
MOA and General Effects:
MOA: block access of AChE active site, preventing the breakdown of ACh and magnifying response to physiologically released ACh
IN order for these drugs to be effective cholinergic synapses must be INTACT and FUNCTIONAL
CHOLINESTERASE INHIBITION:
2 classes, examples
Reversible: bind non-covalently to active site of are slowly hydrolyzed by enzyme and therefore only result in temporary inhibition (less than 3 hours)
Physostigmine* Neostigmine* Pyridostigmine Edrophonium Rivastigmine Donepezil Galantamine
Irreversible (Organophosphates): form extremely stable covalent bonds with the esteratic site, resulting in extremely long half-lives (hours to days) and a prolonged duration of action (reversal requires synthesis of new AChE)
Echothiophate*
Malathion (insecticide)
Parathion (insecticide)
Sarin (nerve gas)
Reversible Anticholinesterase Agents:
MOA
Prototypes
MOA: poor substrates for AChE (hydrolyzed slowly) or simple competitive inhibitors of ACh binding
Prototypes:
Physostigmine
Neostigmine
Physostigmine:
Structure
Action
Use
Metabolism
Structure:
natural tertiary amine methyl carbamate
Action:
almost exclusive to AChE at both muscarinic and nicotinic junctions
- Binds covalently at active site of AChE, but is slowly hydrolyzed (reversible)
Use:
- Topical miotic agent in treatment of glaucoma
- Systemic administration for reversal of toxic CNS/peripheral effects of muscarinic blocking agents during OD (atropine, TCAs)
o Not so much anymore due to physostigmine’s potential to cause seizures
Metabolism: ester hydrolysis in the plasma compartment
Neostigmine:
Structure
Action
Binds covalently where:
Stipulation of action:
- Myasthenia gravis?
Structure: synthetic quaternary amine analog of physostigmine
- Therefore, no CNS effects (ie. no seizure potential)
Action:
anticholinesterase activity + some direct agonist action at nAChR
- Binds covalently at active site of AChE, but is slowly hydrolyzed (reversible)
- Stipulation of action only at intact/functional cholinergic synapses may not be entirely true for this drug (can act as direct agonist at synapses not releases ACh)
-Direct agonist action mediated by charged quaternary amine- makes it more effective for management of NM disease like myasthenia gravis
Neostigmine:
Use
Contraindications
Administration
Metabolism
Use:
- Augment motility of GI tract or lower urinary tract
- Reversing skeletal muscle blockade by competitive antagonists
- May also use edrophonium
- Treatment of mysasthenia gravis
o May also use pyridostigmine
Contraindications: cases of mechanical obstruction of GI tract (increased pressure may cause perforation of gut)
Administration: can be given orally but requires much higher doses (1:15 parenteral to enteral ratio)
Metabolism: ester hydrolysis in plasma compartment
Myasthenia Gravis:
General:
Abs bind where?
What improves the strength of contraction in people with this disease?
Congenital form:
Characterized by skeletal muscle weakness that becomes more intense with exercise or as the day progresses
o May progress to point where it is life-threatening
o Auto-immmune disease (Abs bind to nAChRs on motor endplate)
AChE inhibitors improve the strength of contraction in people with this disease
o Congenital form due to various mutations in the nicotinic receptor (~10%)
- Do not benefit from AChE inhibitors
Edrophonium:
Structure Action - Occupies what site? - Potent direct acting agent where: - Where is systemic action? - Duration of action
Structure: synthetic quaternary amine
Action:
Occupies the anionic site of AChE (non-covalent binding) without affecting the esteratic site
Potent direct acting agent at nAChRs on motor endplate
Therefore, systemic action primarily on skeletal muscles with little/no effects at other cholinergic sites (at therapeutic doses)
Duration of action very short (5 minutes)
